FDA Approves Dinutuximab for High-Risk Neuroblastoma

Richard Pazdur, MD

The FDA has approved dinutuximab (Unituxin) in combination with interleukin-2, GM-CSF, and isotretinoin as a frontline therapy for pediatric patients with high-risk neuroblastoma who responded to prior induction therapy.

Dinutuximab is the first therapy specifically approved for neuroblastoma. The decision was based on data from the phase III ANBL0032 study, which showed an event-free survival (EFS) rate of 63% with dinutuximab plus isotretinoin compared with 46% in patients treated with isotretinoin alone. Overall survival (OS) was improved by 42% with the addition of dinutuximab.

“Unituxin marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Unituxin fulfills a critical need by providing a treatment option that prolongs survival in children with high-risk neuroblastoma.”

In the ANBL0032 study, 226 patients with newly diagnosed high-risk neuroblastoma were randomized to receive dinutuximab plus isotretinoin (n = 113) or isotretinoin alone (n = 113). Patients in the study had received induction therapy and myeloablative consolidation with stem cell rescue. The median age of patients was 3.8 years.

In the investigational arm, patients received dinutuximab at 17.5 mg/m² as a diluted intravenous infusion over 10 to 20 hours. For cycles 1, 3, and 5, dinutuximab was administered in combination with GM-CSF and isotretinoin. In cycles 2 and 4, dinutuximab was given with interleukin-2 and isotretinoin. In cycle 6, isotretinoin and dinutuximab were administered alone.

The investigator-assessed median EFS was not reached in the dinutuximab arm compared with 1.9 years with isotretinoin alone (HR = 0.57; 95% CI, 0.37-0.89; P = .01). At the most recent analysis, four patients on the isotretinoin arm crossed over to receive dinutuximab. The median OS has not yet been reached for either arm (HR = 0.58; 95% CI, 0.37-0.91).

“The FDA approval of dinutuximab represents the culmination of a remarkably productive collaboration between researchers of the NCI-supported Children's Oncology Group, the manufacturing and clinical research groups of NCI, and the oncology team at United Therapeutics,” Malcolm Smith, MD, PhD, associate branch chief, Pediatrics in the Cancer Therapy Evaluation Program at NCI, said in a statement. “Children with neuroblastoma will benefit from this collaboration, and the drug development pathway blazed by dinutuximab will likely be followed in the future to develop other novel agents directed against pediatric cancer therapeutic targets.”

Dinutuximab was approved along with a Boxed Warning regarding nerve cell irritation, which could cause severe pain and nerve damage. Additionally, the treatment could cause life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion.

Comprehensive side effect management is required to manage the adverse events associated with dinutuximab. To mitigate neuropathic pain, intravenous opioids are required before, during, and 2 hours after dinutuximab infusion. Additionally, intravenous hydration and premedication with antihistamines, analgesics, and antipyretics, is required.

The most common all-grade adverse events with dinutuximab versus dinutuximab plus isotretinoin were pain (85% vs 16%), pyrexia (72% vs 27%), thrombocytopenia (66% vs 43%), lymphopenia (62% vs 36%), infusion reactions (60% vs 9%), hypotension (60% vs 3%), hyponatremia (58% vs 12%), increased alanine aminotransferase (56% vs 31%), anemia (51% vs 22%), vomiting (46% vs 19%), diarrhea (43% vs 15%), hypokalemia (43% vs 4%), capillary leak syndrome (40% vs 1%), neutropenia (39% vs 16%), urticaria (37% vs 3%), hypoalbuminemia (33% vs 3%), increased aspartate aminotransferase (28% vs 7%), and hypocalcemia (27% vs 0%).

The most common serious adverse reactions are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

"After decades of pursuits, I am pleased to see that dinutuximab has received FDA approval and may now benefit high risk neuroblastoma patients," lead investigator of the ANBL0032 study Alice Yu, MD, PhD, University of California San Diego, said in a statement. "This is not only the first successful immunotherapeutic to target a non-protein antigen, but also to be developed from an Investigational New Drug Application through phase III trials largely through investigator-initiated effort and NCI support."

Dinutuximab is a chimeric monoclonal antibody that binds to ganglioside GD2, which is commonly overexpressed in malignant melanoma, neuroblastoma, osteosarcoma, and small cell lung cancer. Ongoing studies, including phase III investigations, continue to assess dinutuximab in various combinations for patients with neuroblastoma.